9Y2C
Cryo-EM structure of the human TRPM4 channel subunit in complex with calcium and DAB at 37 degrees Celsius
This is a non-PDB format compatible entry.
Summary for 9Y2C
| Entry DOI | 10.2210/pdb9y2c/pdb |
| EMDB information | 72407 |
| Descriptor | Transient receptor potential cation channel subfamily M member 4, CALCIUM ION, 4,4'-[(pyridin-2-yl)methylene]diphenol (3 entities in total) |
| Functional Keywords | ion channel, trp channel, membrane protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 134813.96 |
| Authors | |
| Primary citation | Liu, Y.,Hu, J.,Xue, C.,Huang, W.,Ievleva, S.,Lu, W.,Du, J.,Cao, Z. Noncanonical calcium-independent TRPM4 activation governs intestinal fluid homeostasis. Nat Commun, 2026 Cited by PubMed Abstract: Imbalance in intestinal fluid homeostasis leads to nutrient malabsorption, intestinal tissue destruction, and systemic inflammation. Transient receptor potential melastatin 4 (TRPM4) is a calcium-activated, non-selective monovalent cation channel converting chemical signals (Ca) into electrical signals (membrane depolarization). Here, we show the TRPM4 channel as a direct target of bisacodyl (BIC), a widely used clinical drug for chronic constipation management, and its active metabolite, deacetyl bisacodyl (DAB). DAB-induced laxative effects are abolished in global and intestinal epithelium-specific TRPM4-knockout mice, establishing the essential role of TRPM4 in intestinal fluid regulation. Furthermore, our structural work reveals DAB bound to an uncharacterized pocket, marking it as a non-Ca TRPM4 agonist and unveiling a noncanonical Ca-independent activation mechanism. Additionally, we delineate a signaling axis, TRPM4 → VGCC/NCX → ANO1, that governs ion homeostasis in the epithelium. Together, these findings establish TRPM4 as a key regulator of intestinal fluid balance and reveal its noncanonical calcium-independent activation as a therapeutic strategy for constipation. PubMed: 41507162DOI: 10.1038/s41467-025-68014-7 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.4 Å) |
Structure validation
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